NMS is caused almost exclusively by antipsychotics, which includes all types of neuroleptic medicines along with newer antipsychotic drugs. The higher the dosage, the more common the occurrence. Rapid and large increases in dosage can also be attributed to the development of NMS.

Other drugs, environmental or psychological factors, hereditary conditions, and specific demographics may be at greater risk, but to date no conclusive evidence has been found to support this. The disorder typically develops within two weeks of the initial treatment with the drug, but may develop at any time that the drug is being taken. NMS may also occur in people taking a class of drugs known as dopaminergics.